Download PDF
Aktuelle Rheumatologie 2023; 48(05): 332-338
DOI: 10.1055/a-2143-1290
Übersichtsarbeit

Rheumatoide Arthritis und das intestinale Mikrobiom – Ein potentieller Faktor in der Pathogenese der RA

Rheumatoid arthritis and the intestinal microbiome – a potential factor involved in the pathogenesis of RA
Christina Heidt
1   Westfälische Wilhelms-Universität Münster, Münster, Deutschland
,
Monika Reuss-Borst
2   Schwerpunkt-Praxis für Rheumatologie, Bad Bocklet, Deutschland
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Zusammenfassung

Die rheumatoide Arthritis (RA) ist eine chronische, entzündliche, systemische Autoimmunerkrankung, die chronisch progredient verläuft und zu schweren strukturellen Schäden und Funktionseinschränkungen führen kann. Ihre Pathogenese ist komplex und nicht abschließend verstanden. Neben genetischen, scheinen vor allem Umweltfaktoren eine wichtige Rolle zu spielen. Der Darm bildet die „innere Grenze“ zur Umwelt und kommt mit vielen Umweltfaktoren in Kontakt. Daher rückt der Darm in den letzten Jahren und mit ihm das Mikrobiom zunehmend (wieder) in den Fokus der Wissenschaft. Immer mehr evidente Befunde zeigen, dass die Mikrobiom-Darm-Gelenk-Achse eine wichtige Rolle bei der RA darstellt. Mikrobielle Dysbiose sowie eine intakte Darmbarriere („leaky gut“) und daraus resultierende bakterielle Translokation stellen potentielle Faktoren in der RA-Pathogenese dar. Hier fassen wir die derzeit bekannte Rolle der intestinalen Mikrobiota für Entstehung und Verlauf der RA zusammen. Wir betrachten dabei die neuesten Erkenntnisse auf dem Gebiet der Mikrobiomforschung und beschreiben den Zusammenhang zwischen intestinaler Dysbiose, intakte Barrierefunktion, bakterielle Translokation, adaptive Immunantwort sowie einen möglichen diätetischen Therapieansatz.

Abstract

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease that is chronically progressive and can lead to severe structural damage and functional impairment. Its pathogenesis is complex and not conclusively understood. Besides genetic factors, environmental factors seem to play an important role. The intestine forms the “inner boundary” with the environment and comes into contact with many environmental factors. Therefore, in recent years, the intestine, and with it the microbiome, have increasingly become a focus of research. More and more evidence shows that the microbiome-gut-joint axis plays an important role in RA. Microbial dysbiosis as well as an intact gut barrier (“leaky gut”) and resulting bacterial translocation are potential factors in RA pathogenesis. Here, we summarize the currently known role of the intestinal microbiota in the development and progression of RA. We review recent findings in the field of microbiome research and describe the relationship between intestinal dysbiosis, intact barrier function, bacterial translocation, adaptive immune response, and a potential dietary therapeutic approach.

Schlüsselwörter

Rheumatoide Arthritis - intestinale Mikrobiota - Dysbiose - Zonulin - Ballaststoffe

Key words

rheumatoid arthritis - intestinal microbiota - dysbiosis - zonulin - fibre


Publication History

Article published online:
27 September 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Albrecht K, Callhoff J, Strangfeld A. [Is the prevalence of rheumatoid arthritis truly on the rise?]. Z Rheumatol 2022; 81: 323-327
    CrossrefPubMedSearch in Google Scholar
  • 2 Smolen JS, Aletaha D, Barton A. et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018; 4: 18001
    CrossrefPubMedSearch in Google Scholar
  • 3 Steffen A, Holstiege J, Goffrier B. et al. Epidemiologie der rheumatoiden Arthritis in Deutschland – eine Analyse anhand bundesweiter vertragsärztlicher Abrechnungsdaten. Berlin: Zentralinstitut für die kassenärztliche Versorgung in Deutschland (Zi); 2017
    Search in Google Scholar
  • 4 Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016; 388: 2023-2038
    CrossrefPubMedSearch in Google Scholar
  • 5 Rasouli-Saravani A, Jahankhani K, Moradi S. et al. Role of microbiota short-chain fatty acids in the pathogenesis of autoimmune diseases. Biomed Pharmacother 2023; 162: 114620
    CrossrefPubMedSearch in Google Scholar
  • 6 Zaiss MM, Joyce Wu HJ, Mauro D. et al. The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol 2021; 17: 224-237
    CrossrefPubMedSearch in Google Scholar
  • 7 Deane KD, Demoruelle MK, Kelmenson LB. et al. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 2017; 31: 3-18
    CrossrefPubMedSearch in Google Scholar
  • 8 Jin J, Li J, Hou M. et al. A Shifted Urinary Microbiota Associated with Disease Activity and Immune Responses in Rheumatoid Arthritis. Microbiol Spectr 2023; 11: e0366222
    CrossrefPubMedSearch in Google Scholar
  • 9 Attur M, Scher JU, Abramson SB. et al. Role of Intestinal Dysbiosis and Nutrition in Rheumatoid Arthritis. Cells 2022; 11
    CrossrefPubMedSearch in Google Scholar
  • 10 Clemente JC, Manasson J, Scher JU. The role of the gut microbiome in systemic inflammatory disease. Bmj 2018; 360: j5145
    CrossrefPubMedSearch in Google Scholar
  • 11 D’Amelio P, Sassi F. Gut Microbiota, Immune System, and Bone. Calcif Tissue Int 2018; 102: 415-425
    CrossrefPubMedSearch in Google Scholar
  • 12 Wu X, He B, Liu J. et al. Molecular Insight into Gut Microbiota and Rheumatoid Arthritis. Int J Mol Sci 2016; 17: 431
    CrossrefPubMedSearch in Google Scholar
  • 13 Tanoue T, Atarashi K, Honda K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 2016; 16: 295-309
    CrossrefPubMedSearch in Google Scholar
  • 14 Matei DE, Menon M, Alber DG. et al. Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Med 2021; 2: 864-883.e869
    CrossrefPubMedSearch in Google Scholar
  • 15 Ding Q, Hu W, Wang R. et al. Signaling pathways in rheumatoid arthritis: Implications for targeted therapy. Signal Transduction and Targeted Therapy 2023; 8: 68
    CrossrefPubMedSearch in Google Scholar
  • 16 Shapira M. Gut Microbiotas and Host Evolution: Scaling Up Symbiosis. Trends Ecol Evol 2016; 31: 539-549
    CrossrefPubMedSearch in Google Scholar
  • 17 Gomaa EZ. Human gut microbiota/microbiome in health and diseases: a review. Antonie Van Leeuwenhoek 2020; 113: 2019-2040
    CrossrefPubMedSearch in Google Scholar
  • 18 Qin J, Li R, Raes J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464: 59-65
    CrossrefPubMedSearch in Google Scholar
  • 19 Zafar H, Saier MH. Gut Bacteroides species in health and disease. Gut Microbes 2021; 13: 1-20
    CrossrefPubMedSearch in Google Scholar
  • 20 Quigley EMM. Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet?. Nat Rev Gastroenterol Hepatol 2017; 14: 315-320
    CrossrefPubMedSearch in Google Scholar
  • 21 Weiss GA, Hennet T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci 2017; 74: 2959-2977
    CrossrefPubMedSearch in Google Scholar
  • 22 Scher JU, Sczesnak A, Longman RS. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2013; 2: e01202
    CrossrefPubMedSearch in Google Scholar
  • 23 Zhang X, Zhang D, Jia H. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21: 895-905
    CrossrefPubMedSearch in Google Scholar
  • 24 Chen J, Wright K, Davis JM. et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med 2016; 8: 43
    CrossrefPubMedSearch in Google Scholar
  • 25 Maeda Y, Kurakawa T, Umemoto E. et al. Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine. Arthritis Rheumatol 2016; 68: 2646-2661
    CrossrefPubMedSearch in Google Scholar
  • 26 Chiang HI, Li JR, Liu CC. et al. An Association of Gut Microbiota with Different Phenotypes in Chinese Patients with Rheumatoid Arthritis. J Clin Med 2019; 8
    CrossrefPubMedSearch in Google Scholar
  • 27 Zhang J, Fang XY, Leng R. et al. Metabolic Signature of Healthy Lifestyle and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Study. Am J Clin Nutr 2023; 118: 183-193
    CrossrefPubMedSearch in Google Scholar
  • 28 Horta-Baas G, Romero-Figueroa MDS, Montiel-Jarquín AJ. et al. Intestinal Dysbiosis and Rheumatoid Arthritis: A Link between Gut Microbiota and the Pathogenesis of Rheumatoid Arthritis. J Immunol Res 2017; 2017: 4835189
    CrossrefPubMedSearch in Google Scholar
  • 29 Pianta A, Arvikar SL, Strle K. et al. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest 2017; 127: 2946-2956
    CrossrefPubMedSearch in Google Scholar
  • 30 Tajik N, Frech M, Schulz O. et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun 2020; 11: 1995
    CrossrefPubMedSearch in Google Scholar
  • 31 Brandl C, Bucci L, Schett G. et al. Crossing the barriers: Revisiting the gut feeling in rheumatoid arthritis. Eur J Immunol 2021; 51: 798-810
    CrossrefPubMedSearch in Google Scholar
  • 32 Audo R, Sanchez P, Rivière B. et al Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation which are reversed by inflammation control. Rheumatology (Oxford) 2022; 10.1093/rheumatology/keac454
    CrossrefPubMedSearch in Google Scholar
  • 33 Ruff WE, Greiling TM, Kriegel MA. Host-microbiota interactions in immune-mediated diseases. Nat Rev Microbiol 2020; 18: 521-538
    CrossrefPubMedSearch in Google Scholar
  • 34 Zihni C, Mills C, Matter K. et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 2016; 17: 564-580
    CrossrefPubMedSearch in Google Scholar
  • 35 Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 2016; 4: e1251384
    CrossrefPubMedSearch in Google Scholar
  • 36 Heidt C, Kämmerer U, Fobker M. et al. Assessment of Intestinal Permeability and Inflammation Bio-Markers in Patients with Rheumatoid Arthritis. Nutrients 2023; 15
    CrossrefPubMedSearch in Google Scholar
  • 37 Smyth MC. Intestinal permeability and autoimmune diseases. Bioscience Horizons: The International Journal of Student Research 2017; 10
    PubMedSearch in Google Scholar
  • 38 Tulkens J, Vergauwen G, Van Deun J. et al. Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut 2020; 69: 191-193
    CrossrefPubMedSearch in Google Scholar
  • 39 Yoon JH, Do JS, Velankanni P. et al. Gut Microbial Metabolites on Host Immune Responses in Health and Disease. Immune Netw 2023; 23: e6
    CrossrefPubMedSearch in Google Scholar
  • 40 Gentile CL, Weir TL. The gut microbiota at the intersection of diet and human health. Science 2018; 362: 776-780
    CrossrefPubMedSearch in Google Scholar
  • 41 Cummings JH, Macfarlane GT, Englyst HN. Prebiotic digestion and fermentation. Am J Clin Nutr 2001; 73: 415s-420s
    CrossrefPubMedSearch in Google Scholar
  • 42 Hui W, Yu D, Cao Z. et al. Butyrate inhibit collagen-induced arthritis via Treg/IL-10/Th17 axis. Int Immunopharmacol 2019; 68: 226-233
    CrossrefPubMedSearch in Google Scholar
  • 43 Lucas S, Omata Y, Hofmann J. et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun 2018; 9: 55
    CrossrefPubMedSearch in Google Scholar
  • 44 Häger J, Bang H, Hagen M. et al. The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study. Nutrients 2019; 11
    CrossrefPubMedSearch in Google Scholar
  • 45 Makki K, Deehan EC, Walter J. et al. The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease. Cell Host Microbe 2018; 23: 705-715
    CrossrefPubMedSearch in Google Scholar
  • 46 De Filippo C, Cavalieri D, Di Paola M. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 2010; 107: 14691-14696
    CrossrefPubMedSearch in Google Scholar
  • 47 Walker AW, Parkhill J. Microbiology. Fighting obesity with bacteria. Science 2013; 341: 1069-1070
    CrossrefPubMedSearch in Google Scholar
  • 48 Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-249
    CrossrefPubMedSearch in Google Scholar
  • 49 Goodrich JK, Davenport ER, Waters JL. et al. Cross-species comparisons of host genetic associations with the microbiome. Science 2016; 352: 532-535
    CrossrefPubMedSearch in Google Scholar
  • 50 Neumann E, Frommer K, Diller M. et al. Rheumatoide Arthritis. Zeitschrift für Rheumatologie 2018; 77: 769-775
    CrossrefPubMedSearch in Google Scholar
  • 51 Fournier C. Where do T cells stand in rheumatoid arthritis?. Joint Bone Spine 2005; 72: 527-532
    CrossrefPubMedSearch in Google Scholar
  • 52 Glatigny S, Blaton MA, Mencher SK. et al. Treatment of collagen-induced arthritis by Natura-alpha via regulation of Th-1/Th-17 responses. Eur J Immunol 2010; 40: 460-469
    CrossrefPubMedSearch in Google Scholar
  • 53 Leung S, Liu X, Fang L. et al. The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol 2010; 7: 182-189
    CrossrefPubMedSearch in Google Scholar
  • 54 Tuncel J, Haag S, Holmdahl R. MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis. European journal of immunology 2017; 47: 563-574
    CrossrefPubMedSearch in Google Scholar
  • 55 Wang L, Wang Y, Liu C. et al. Treg-targeted efficient-inducible platform for collagen-induced arthritis treatment. Mater Today Bio 2023; 19: 100557
    CrossrefPubMedSearch in Google Scholar
  • 56 Savage PA, Klawon DEJ, Miller CH. Regulatory T Cell Development. Annu Rev Immunol 2020; 38: 421-453
    CrossrefPubMedSearch in Google Scholar
  • 57 Samson M, Audia S, Janikashvili N. et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum 2012; 64: 2499-2503
    CrossrefPubMedSearch in Google Scholar
  • 58 Gao B, Chi L, Zhu Y. et al. An Introduction to Next Generation Sequencing Bioinformatic Analysis in Gut Microbiome Studies. Biomolecules 2021; 11
    CrossrefPubMedSearch in Google Scholar
  • 59 Kageyama T, Matsuo T, Kurakake R. et al. Relationship between T cells and microbiota in health and disease. Prog Mol Biol Transl Sci 2020; 171: 95-129
    CrossrefPubMedSearch in Google Scholar
  • 60 Keyßer G, Michalsen A, Reuß-Borst M. et al. Empfehlungen der Kommission Komplementäre Heilverfahren und Ernährung zu ayurvedischer Medizin, Homöopathie, Ernährung und mediterraner Kost. Zeitschrift für Rheumatologie 2023; 1-14
    PubMedSearch in Google Scholar
  • 61 Schriefer AE, Cliften PF, Hibberd MC. et al. A multi-amplicon 16S rRNA sequencing and analysis method for improved taxonomic profiling of bacterial communities. J Microbiol Methods 2018; 154: 6-13
    CrossrefPubMedSearch in Google Scholar
  • 62 Scher JU, Nayak RR, Ubeda C. et al. Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response. Nat Rev Rheumatol 2020; 16: 282-292
    CrossrefPubMedSearch in Google Scholar
  • 63 Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut 2020; 69: 1510-1519
    CrossrefPubMedSearch in Google Scholar
  • 64 Osler W. The principles and practice of medicine: designed for the use of practitioners and students of medicine: D. Appleton. 1910
    PubMedSearch in Google Scholar
  • 65 Warden CC. The Toxemic Factor In Rheumatoid Arthritis. Cal State J Med 1909; 7: 299-301
    PubMedSearch in Google Scholar
  • 66 BARGEN JA. Complications and sequelae of chronic ulcerative colitis. Annals of Internal Medicine 1929; 3: 335-352
    CrossrefPubMedSearch in Google Scholar
  • 67 Mielants H, Veys EM, Cuvelier C. et al. The evolution of spondyloarthropathies in relation to gut histology. III. Relation between gut and joint. J Rheumatol 1995; 22: 2279-2284
    PubMedSearch in Google Scholar
  • 68 Blenkinsopp HC, Seidler K, Barrow M. Microbial Imbalance and Intestinal Permeability in the Pathogenesis of Rheumatoid Arthritis: A Mechanism Review with a Focus on Bacterial Translocation, Citrullination, and Probiotic Intervention. J Am Nutr Assoc 2023; 1-18. 10.1080/27697061.2023.2211129
    CrossrefPubMedSearch in Google Scholar